Project Summary Children develop less severe COVID-19 disease than adults. Many children who become infected may develop asymptomatic infection, but most testing has been done in symptomatic individuals. The epidemiology of SARS-CoV-2 in children, spectrum of illness and risk factors for infection or disease are poorly understood, especially in LMICs. Further, recent data suggest that prior endemic coronavirus infection may protect against SARS-CoV-2 infection or disease.4 Additional research to address these issues is urgently needed, given the childhood populations in LMICs, the need to better understand the role of children in community transmission and the role of antibodies in protection in the current epidemic and in future waves. We will leverage the Drakenstein Child Health Study cohort, capitalizing on a very well phenotyped population with high cohort retention, comprehensive longitudinal measurement of risk factors and a large biobank of samples, to prospectively investigate the epidemiology and risk factors for COVID-19 in children and serological responses (including false-positive testing with SARS-CoV-2 assays and cross-protective immunity). Further, since we have longitudinally documented infection with the four endemic coronaviruses in this cohort, we are uniquely placed to investigate the potential protective effect of prior endemic human coronavirus (nHCoV) infection on SARS-CoV-2. All children in the Drakenstein cohort (n=900) will have study visits at three timepoints (0, 3 and 6 months) to collect clinical and risk factor data and specimens (nasal and serum). Risk factors for infection or disease will be collected, including environmental, nutritional, sociodemographic, maternal health, infectious exposures (including TB infection) and underlying illness. We will also test the most recent biobanked serum from each child collected before the COVID-19 epidemic (before March 2020) as well as selected biobanked convalescent serum samples from children with confirmed recent endemic (-229E, -NL63, -OC43, and -HKU1) coronavirus infection with serological tests for SARS-CoV-2. Where there is evidence of cross-reactive antibody responses these will be further characterized by Western Blot and Plaque Reduction Neutralization Test. In addition, children presenting for care with intercurrent LRTI will have nasal and blood samples and an induced sputum specimen collected, and tested.